Self-assembled PROTACs enable protein degradation to reprogram the tumor microenvironment for synergistically enhanced colorectal cancer immunotherapy.

Both ß-catenin and STAT3 drive colorectal cancer (CRC) growth, progression, and immune evasion, and their co-overexpression is strongly associated with a poor prognosis. However, current small molecule inhibitors have limited efficacy due to the reciprocal feedback activation between STAT3 and ß-catenin. Inspired by the PROteolysis TArgeting Chimera (PROTAC), a promising pharmacological modality for the selective degradation of proteins, we developed a strategy of nanoengineered peptide PROTACs (NP-PROTACs) to degrade both ß-catenin and STAT3 effectively. The NP-PROTACs were engineered by coupling the peptide PROTACs with DSPE-PEG via disulfide bonds and self-assembled into nanoparticles. Notably, the dual degradation of ß-catenin and STAT3 mediated by NP-PROTACs led to a synergistic antitumor effect compared to single-target treatment. Moreover, NP-PROTACs treatment enhanced CD103+ dendritic cell infiltration and T-cell cytotoxicity, alleviating the immunosuppressive microenvironment induced by ß-catenin/STAT3 in CRC. These results highlight the potential of NP-PROTACs in facilitating the simultaneous degradation of two pathogenic proteins, thereby providing a novel avenue for cancer therapy.

Liver-expressed antimicrobial peptide 2 is a hepatokine regulated by ghrelin, nutrients, and body weight.

Liver-expressed antimicrobial peptide 2 (LEAP2) is a peptide that counteracts the hunger hormone ghrelin-induced functions. Recently, we showed that vertical sleeve gastrectomy (VSG) did not alter the serum LEAP2 concentration in individuals with obesity. Here, we investigated the effects of VSG in both chow diet (CD)-fed and high-fat diet (HFD)-fed mice. In CD-fed mice, VSG increased plasma LEAP2 levels and hepatic Leap2 mRNA levels while decreasing body weight, blood glucose levels, and ghrelin levels. Intraperitoneal (ip) administration of ghrelin reversed these changes. These effects were found in both male and female mice. In contrast, VSG or weight loss in HFD-induced obese mice decreased LEAP2 levels. After fasting, the plasma LEAP2 concentration was in the following order: hepatic vein > abdominal aorta > portal vein. A high glucose concentration robustly increased the plasma LEAP2 concentration in the hepatic vein and abdominal aorta but not in the portal vein. In addition, corn oil or palmitate increased LEAP2 expression and secretion. The increase in LEAP2 levels after the meal tolerance test was delayed in the human subjects with diabetes. Our data suggest that various factors (metabolic, hormonal, and nutritional) regulate LEAP2, and the liver is the predominant site for the production and secretion of LEAP2. Furthermore, the interaction between ghrelin and LEAP2 is involved in the pathogenesis of obesity and diabetes.

Aß -induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases.

Alzheimer's diseases (AD) patients suffer from more serious bone loss than cognitively normal subjects at the same age. Type H blood vessels were tightly associated with bone homeostasis. However, few studies have concentrated on bone vascular alteration and its role in AD-related bone loss. In this study, APP/PS1 mice (4- and 8-month-old) and age-matched wild-type mice were used to assess the bone vascular alteration and its role in AD-related bone loss. Transmission electron microscopy, immunofluorescence staining and iGPS 1.0 software database were utilized to investigate the molecular mechanism. Mitochondrial division inhibitor (Mdivi-1) and GSK-3ß inhibitor (LiCl) were used to rescue type H blood vessels injury and verify the molecular mechanism. Our results revealed that APP/PS1 mice exhibited more serious bone blood vessels injury and bone loss during ageing. The bone blood vessel injury, especially in type H blood vessels, was accompanied by impaired vascularized osteogenesis in APP/PS1 mice. Further exploration indicated that beta-amyloid (Aß) promoted the apoptosis of vascular endothelial cells (ECs) and resulted in type H blood vessels injury. Mechanistically, Aß-induced excessive mitochondrial fission was found to be essential for the apoptosis of ECs. GSK-3ß was identified as a key regulatory target of Aß-induced excessive mitochondrial fission and bone loss. The findings delineated that Aß-induced excessive mitochondrial fission drives type H blood vessels injury, leading to aggravate bone loss in APP/PS1 mice and GSK-3ß inhibitor emerges as a potential therapeutic strategy.

Experimental studies on the cooling and heating performance of a highly emissive coating.

In this study, the cooling effect below ambient air temperature, heat dissipation properties and heating energy efficacy of a superomniphobic self-cleaning (SSC) highly emissive (HE) coating were systematically investigated. Except at midday, the SSC-HE coating with an extremely high solar reflectance of 0.985 showed a better cooling effect than a 10-cm-thick polyurethane insulation layer. The coating substantially reduced the interior air temperature of a well-insulated system by as much as 6.9 °C. The SSC-HE coating enabled the roof surface and room temperatures of the brick bungalow to be 3.4 and 10.2 °C below the ambient air temperature, respectively. Compared with the sunshade and spray water, the SSC-HE coating exhibited better cooling effect. The SSC topcoat allowed the battery cabinet of an HE-coated distributed telecommunication base station to remain its original sub-ambient cooling effect for a long time. Regardless of the location of the HE-coated metal facility, the ultrahigh emissivity of the coating enabled it to exhibit excellent heat dissipation performance during both day and night, even under adiabatic conditions. Additionally, under identical room temperature settings, the HE-coated electric oil heater not only showed faster heating but also had heating energy efficiency of 5.9 % and 4.4 % relative to heaters coated with aluminium- and black paints, respectively. Under identical heating power consumption levels, compared to black paint-coated heater, the HE-coated heater endowed the surrounding environment with a higher equilibrium air temperature, improving the thermal comfort of the indoor environment.

Impairment of Internal Auditory Canal Barrier in Meniere's Disease.

OBJECTIVE: The aim of this investigation was to explore the potential correlation between the signal intensity ratio (SIR) at the internal auditory canal (IAC) fundus and hearing impairment in Meniere's disease (MD), thereby providing a foundation to further understand the mechanisms underlying hearing loss. DESIGN: Fifty patients diagnosed with unilateral definite MD were enrolled in the study. 3D-FLAIR MRI was conducted 4 h after intravenous administration of gadobutrol to determine the SIR of the bilateral IAC fundus. The difference in the SIR of the IAC fundus between the affected and unaffected sides was assessed, followed by an analysis of its correlation with low-, middle-, and high-tone hearing thresholds. Correlation analysis was also conducted between the degree of endolymphatic hydrops (EH) in the vestibule and cochlea and the SIR on the affected side. RESULTS: The degree of EH in MD can be clearly visualised using 3D-FLAIR MRI. The SIR on the affected side was significantly higher than that on the unaffected side (p = 0.000). Furthermore, a positive correlation was observed between the SIR at the affected and low (r = 0.692, p = 0.000), middle (r = 0.615, p = 0.000) and high-tone (r = 0.440, p = 0.001) hearing thresholds, while the SIR showed no significant correlation with cochlear (r = 0.315, p = 0.088) or vestibular hydrops (r = 0.215, p = 0.244). CONCLUSION: The IAC fundus barrier may be damaged in patients with MD, representing one of the factors affecting the level of hearing.

Deciphering the role of PLCD3 in lung cancer: A gateway to glycolytic reprogramming via PKC-Rap1 activation.

PLCD3 belongs to the phospholipase C delta group and is involved in numerous biological functions, including cell growth, programmed cell death, and specialization. However, the role of PLCD3 in lung cancer still needs further investigation. This research aimed to investigate if PLCD3 influences glycolytic reprogramming and lung cancer development through the PKC-dependent Rap1 signaling pathway. This study found that PLCD3 was increased in lung cancer tissues. PLCD3 promotes the proliferation and invasion of lung cancer cells by activating the PKC-dependent Rap1 pathway. The detailed process involves PLCD3 triggering PKC, which subsequently stimulates the Rap1 pathway, leading to glycolytic reprogramming that supplies adequate energy and metabolic substrates necessary for the growth and spread of lung cancer cells. Moreover, PLCD3 can also promote the metastasis and invasion of lung cancer cells by activating the Rap1 pathway. This study reveals the mechanism of PLCD3 in lung cancer and provides new ideas for the treatment of lung cancer. Inhibiting PLCD3, PKC, and the Rap1 pathway may be an effective strategy for treating lung cancer.

In-Depth Analysis of Molecular Network Based on Liquid Chromatography Coupled with Tandem Mass Spectrometry in Natural Products: Importance of Redundant Nodes Discovery.

The identification of molecules within complex mixtures is a major bottleneck in natural products (NPs) research. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as the main tool for the high-throughput characterization of NPs. The large amount of data sets by LC-MS/MS presents a challenge for data processing and interpretation, and the LC-MS/MS molecular network (MN) is one of the most prominent tools for analyzing large MS/MS data sets, widely used for rapid classification, identification, and structural speculation of unknown compounds. However, the existence of a large number of redundant nodes leads to false-positive results. To solve this problem, we proposed the in-depth analysis of MN. In this study, in-depth analysis of MN of five NPs representing the common structures of saponin, steroid, flavonoid, alkaloid, and phenolic acid revealed the presence of redundant nodes (including other adducts, isotope, and in-source fragmentation) in addition to the normal nodes, which can lead to false-positive identification results. Additionally, the reasons for different redundant nodes are discussed and experimentally verified, and it was found that the impact of redundant nodes can be mitigated by optimizing the experimental conditions and employing Feature-Based Molecular Networking. Furthermore, Ion Identity Molecular Networking can rapidly discover and screen redundant nodes, simplifying the in-depth analysis of MN and improving the network connectivity of structurally related molecules. Finally, a combination formulation of 7 NPs is used as an example to provide a guide for in-depth analysis of MN for comprehensive characterization of complex systems. This study highlights the importance of an in-depth analysis of MN for better understanding and utilization of MS/MS data in complex systems to reduce the false-positive rate of identification by screening and filtering redundant nodes.

Insights into therapeutic peptides in the cancer-immunity cycle: Update and challenges.

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.

Explainable Fault Diagnosis Using Invertible Neural Networks-Part I: A Left Manifold-Based Solution.

The series includes two parts, articulating the two novel avenues of research on intelligent fault diagnosis (FD) for nonlinear feedback control systems. In Part I of the series, we design a novel FD paradigm by elaborating an invertible neural network (INN) for feedback control systems. With the aid of a left manifold, the core idea behind the INN-based FD scheme is as follows: 1) formulation of residual generator used for FD as a projection of system data onto the null space that has the same dimension as system outputs; 2) in a topological space, elaboration of a homeomorphism that delivers an invertible relationship between system outputs and residual signals when the system input is given; and 3) skillful introduction of both the master and slave objective functions to achieve system/parameter identification with information loseless property. Comparing with the existing FD approaches, the three superior strengths of the proposed FD scheme deserving mentation are as follows: 1) it specializes in nonlinear feedback control systems; 2) it can effectively avoid the overfitting problem when approximating or learning nonlinear system dynamics; and 3) control theory guides the whole design, ensuring the interpretability of the learning process. Finally, two studies on nonlinear systems demonstrate the feasibility of the invertible left manifold (ILM)-based FD strategy. Part I would contribute to the future development of machine learning (ML)-based system identification and explainable FD approaches, and also benefits the right manifold-based FD designs in Part II.

[Thulium laser enucleation versus plasma kinetic resection of the prostate in the treatment of benign prostatic hyperplasia].

OBJECTIVE: To compare thulium laser enucleation of the prostate (ThuLEP) with plasma kinetic resection of the prostate (PKRP) in the treatment of BPH. METHODS: We retrospectively analyzed the medical records of 160 cases of BPH treated by ThuLEP (the observation group, n = 80) or PKRP (the control group, n = 80) in our hospital from January 2021 to December 2023. We recorded the operation time, bladder irrigation time, catheter retention time, hospitalization time, postoperative complications, and pre- and postoperative maximum urinary flow rate (Qmax), residual urine volume (PVR), prostate-specific antigen (PSA) and prostate volume, followed by comparison of the data obtained between the two groups of patients. RESULTS: Compared with the controls, the patients of the observation group showed significantly shorter operation time (ï¼»67.25 ± 7.24ï¼½ vs ï¼»60.10 ± 5.15ï¼½ min, P< 0.05), bladder irrigation time (ï¼»46.90 ± 10.77ï¼½ vs ï¼»43.24 ± 6.65ï¼½ h, P< 0.05), catheterization time (ï¼»5.60 ± 1.31ï¼½ vs ï¼»5.03 ± 1.24ï¼½ d, P< 0.05) and hospitalization time (ï¼»7.31 ± 2.00ï¼½ vs ï¼»6.55 ± 1.67ï¼½ d, P< 0.05), higher Qmax (ï¼»18.50 ± 1.24ï¼½ vs ï¼»20.68 ± 1.45ï¼½ ml/s, P< 0.05), lower PVR (ï¼»12.10 ± 3.53ï¼½ vs ï¼»10.82 ± 3.10ï¼½ ml, P< 0.05), PSA (ï¼»4.60 ± 0.78ï¼½ vs ï¼»3.38 ± 0.40ï¼½ µg/L, P< 0.05) and prostate volume (ï¼»25.35 ± 6.46ï¼½ vs ï¼»20.12 ± 5.13ï¼½ ml, P< 0.05) at 3 months after surgery, but no statistically significant difference in the total incidence of postoperative complications (7.50% ï¼»6/80ï¼½ vs 5.00% ï¼»4/80ï¼½, P > 0.05). CONCLUSION: ThuLEP, with its advantages of notable effect, short operation and hospitalization time, significant improvement of urinary flow dynamics and prostate function, deserves clinical promotion for the treatment of BPH.

Comprehensive applications of the artificial intelligence technology in new drug research and development.

Purpose: Target-based strategy is a prevalent means of drug research and development (R&D), since targets provide effector molecules of drug action and offer the foundation of pharmacological investigation. Recently, the artificial intelligence (AI) technology has been utilized in various stages of drug R&D, where AI-assisted experimental methods show higher efficiency than sole experimental ones. It is a critical need to give a comprehensive review of AI applications in drug R &D for biopharmaceutical field. Methods: Relevant literatures about AI-assisted drug R&D were collected from the public databases (Including Google Scholar, Web of Science, PubMed, IEEE Xplore Digital Library, Springer, and ScienceDirect) through a keyword searching strategy with the following terms [("Artificial Intelligence" OR "Knowledge Graph" OR "Machine Learning") AND ("Drug Target Identification" OR "New Drug Development")]. Results: In this review, we first introduced common strategies and novel trends of drug R&D, followed by characteristic description of AI algorithms widely used in drug R&D. Subsequently, we depicted detailed applications of AI algorithms in target identification, lead compound identification and optimization, drug repurposing, and drug analytical platform construction. Finally, we discussed the challenges and prospects of AI-assisted methods for drug discovery. Conclusion: Collectively, this review provides comprehensive overview of AI applications in drug R&D and presents future perspectives for biopharmaceutical field, which may promote the development of drug industry.

A Minimalist Method for Fully Oxygen-Tolerant RAFT Polymerization through Sulfur-Centered Trithiocarbonate Radical Initiation.

In recent years, the fully oxygen-tolerant reversible deactivation radical polymerization (RDRP) has become a highly researched area. In this contribution, a new and minimalist method is successfully employed to accomplish fully oxygen-tolerant reversible addition-fragmentation chain transfer (RAFT) polymerization using bis(trithiocarbonate) disulfides (BisTTC) as an iniferter agent, where the released sulfur-centered trithiocarbonate (TTC) radical can initiate monomer. Furthermore, polymerization kinetics revealed the typical "living" features of this polymerization system. More importantly, by high-throughput screening, it is found that dodecyl-substituted TTC is responsible for the fully oxygen-tolerant RAFT polymerization though trithiocarbonate radical initiation and R radical deoxygenation. It is believed that trithiocarbonate radical initiation strategy provides a powerful and minimalist tool for fully oxygen-tolerant RDRPs.

Access to Diverse Carbonyl Compounds by Catalyst-Free and Photoinduced Aerobic Cleavage of C=N Bonds.

Functional group interconversion is of great significance in organic synthesis. However, aerobic cleavage of C=N bonds to access carbonyl compounds still suffered from some limitations such as harsh reaction conditions, stoichiometric oxidants, poor substrate scope and use of toxic reagents. Herein, we report a catalyst-free and photo-induced aerobic cleavage of C=N bonds to afford diverse carbonyl compounds using oxygen from air as green oxidant. This mild methodology permits N-tosylhydrazones converted into the corresponding carbonyl compounds including ketones, aldehydes and carboxylic acids, showing broad functional group tolerance and compatibility. Moreover, the gram-scale reaction and post-modification of complicated molecules proved the applicability and efficiency of this strategy. Finally, a plausible mechanism was proposed based on spectroscopic investigations and detailed mechanistic studies.

Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate.

Purpose: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial. Methods: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing. Results: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD. Conclusion: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies.

Considerations on Design and Analysis of External Control in Pediatric Oncology.

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

NUAK2 mediated regulation of Schwann Cell proliferation and migration in peripheral nerve injury via YAP.

NUAK2 is a member of the AMP-activated protein kinase (AMPK) family, which plays an essential role in cellular processes such as apoptosis, proliferation, and cell fate. Recent studies have already shown that silencing of NUAK2 blocks proliferation and promotes apoptosis of human melanoma cells and liver cancer cells. In addition, NUAK2 is involved in the development of glioblastoma via regulating the expression of cancer stem cell-related genes, and it promotes the cell cycle entry in the glioblastoma cells. However, the expression and the role of NUAK2 in the progress of peripheral nerve regeneration after injury are yet to be elucidated. We observed that NUAK2 was upregulated following distal sciatic nerve crush (SNC). Interestingly, we discovered that NUAK2 showed co-localization with S100 (Schwann cell marker). Furthermore, we found that the NUAK2 had a spatiotemporal protein expression, which was consistent with proliferating cell nuclear-antigen (PCNA). The protein level of NUAK2 and YAP was upregulated in the model of TNF-α-induced Schwann cell (SC) proliferation. Furthermore, flow cytometry analysis, CCK-8, transwell assays, and wound healing assays were all performed with the purpose of exploring the role of NUAK2 in the regulation of SC proliferation and migration. More importantly, we found that NUAK2-deficient SCs showed significantly reduced expression of Yes-associated protein (YAP). Bioinformatic analysis identified upstream regulators of NUAK2 and NUAK2-associated genes (e.g., YAP1). Finally, we investigated the recovery changes during regeneration progress through the walking track analysis. Thus, we speculated that NUAK2 was involved in biochemical and physiological responses of SCs after SNC via YAP-driven proliferation and migration, and this study determined the importance of NUAK2 as a potential target in peripheral nerve regeneration.

Screening of optimal cleaning methods to reduce microplastic residues on strawberry surfaces: Characterization of microplastics in strawberry wash water.

Microplastics are widespread in facility strawberry greenhouses and can be deposited on the surface of strawberries through air currents. Investigating effective cleaning methods represents a viable strategy to reduce human ingestion of MPs. Therefore, different cleaning methods were compared: ultrasonic cleaning for 30 min, deionized water rinsing once, deionized water immersion for 30 min, and fruit immersion in washing salt for 30 min. The MPs in strawberry washing water were analyzed and compared using laser direct infrared imaging to investigate their characteristics and the optimal reduction of MPs on the surface of strawberries. The quality of the cleaning results was in the following order: water immersion > washing salt immersion > water rinsing > ultrasound. Water immersion was 1.3-2 times more effective in removing microplastics than other treatments. Furthermore, 21 polymer types were detected in the samples. Most MPs were less than 50 µm in size. The main polymers in this size range were polyamide, chlorinated polyethylene, and polyethylene terephthalate, and they mainly existed as fragments, fibers, and beads. This study provides a valuable reference for reducing human intake of microplastics through fresh fruits and vegetables.